It is considered that collagen and proteoglycan as the principal components of mammalian connective tissues are degraded by a matrix metalloprotease (MMP) in a specific fashion and then by other proteolytic enzymes. Examples of known matrix metalloproteases include collagenase (MMP1), gelatinase (MMP2), proteoglycanase (MMP3) and the like. It is also considered that these matrix metalloproteases, together with a tissue inhibitor of metalloprotease (TIMP) as their biological inhibiting factor and .alpha.2-macroglobulin, are taking a great role in controlling metabolism of connective tissues, and that the progress of connective tissue destruction occurs when collagen and proteoglycan are degraded by the matrix metalloprotease formed in an excess amount due to the unbalanced levels of the matrix metalloprotease and the biological inhibiting factor.
In consequence, a matrix metalloprotease inhibitor which represses tissue destruction through its activity to inhibit the aforementioned degradation by matrix metalloproteases will be useful for the prevention and treatment of diseases which are believed to be caused by the progress of connective tissue destruction, such as arthritis (e.g., chronic articular rheumatism and osteoarthritis), periodontal disease, corneal ulcer, epidermolysis bullosa, neoplastic infiltration, abnormal bone resorption and the like.
A number of studies have been conducted on the development of pharmaceutical compounds capable of repressing degradation of collagen through their activity to inhibit enzyme activity of collagenase, and such compounds so far reported are roughly divided into certain phosphoric acid derivatives and hydroxamic acid derivatives.
Especially, with regard to a hydroxamic acid derivative which relates to the compound of the present invention, Japanese Patent Application Toppyo Hei. 4-502008 (international publication WO90/05719) discloses a compound represented by the following general formula as a hydroxamic acid-based collagenase inhibitor. ##STR2## (In the above formula, R.sup.1 represents C.sub.1 -C.sub.6 alkyl, phenyl, thiophenyl, substituted phenyl, phenyl (C.sub.1 -C.sub.6) alkyl, heterocyclyl, (C.sub.1 -C.sub.6) alkylcarbonyl, phenacyl or substituted phenacyl or, when n=0, R.sup.1 is --SR.sup.x where R.sup.x represents the following group, ##STR3## R.sup.2 represents a hydrogen atom:, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, phenyl (C.sub.1 -C.sub.6) alkyl, cycloalkyl (C.sub.1 -C.sub.6) alkyl or cycloalkenyl (C.sub.1 -C.sub.6) alkyl,
R.sup.3 represents an amino acid side chain or C.sub.1 -C.sub.6 alkyl, benzyl, (C.sub.1 -C.sub.6 alkoxy) benzyl, benzyloxy (C.sub.1 -C.sub.6 alkyl) or benzyloxybenzyl, PA1 R.sup.4 represents a hydrogen atom or C.sub.1 -C.sub.6 alkyl, PA1 R.sup.5 represents a hydrogen atom or methyl, PA1 n is an integer of 0, 1 or 2, and PA1 A represents a C.sub.1 -C.sub.6 hydrocarbon chain, optionally substituted by one or more C.sub.1 -C.sub.6 alkyl, phenyl or substituted phenyl.) PA1 R.sup.2, R.sup.3 and R.sup.4: the same or different from one another and each represents a lower alkyl group, PA1 X: an oxygen atom or a sulfur atom, PA1 Y: a single bond or a lower alkylene group), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable hydrate thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
However, when pharmacological, toxicological or physicochemical properties of collagenase inhibitors so far available are taken into consideration, a matrix metalloprotease inhibitor requires further improvement in terms of stable or enhanced in vivo pharmacological activity, extension of its effective range on other matrix metalloproteases, reduction of toxicity, improvement of solubility and the like.